A gene for familial juvenile nephronophthisis (recessive medullary cystic kidney disease) maps to chromosome 2p.

Familial juvenile nephronophthisis (NPH) is a chronic autosomal recessive kidney disease responsible for 15% of end stage renal failure in children. NPH is frequently (16% of cases) associated with Leber amaurosis (termed Senior-Løken syndrome, SLS). Linkage analyses, performed in 22 multiplex NPH families (18 without and 4 with ocular abnormalities), have localized the gene to a region between D2S48 and D2S51 on chromosome 2p. This was confirmed using adjacent microsatellite markers, one of which (AFM220ze3 at the D2S160 locus) gave a lod score of 4.78 at theta = 0.05 in the 18 families with isolated NPH, whereas the same marker excluded linkage with SLS. These results demonstrate linkage of the purely renal form of NPH to chromosome 2p, and suggest that there may be genetic heterogeneity between NPH and SLS.

Lactogenic and somatotropic binding sites in liver membranes of rats with renal insufficiency.

Binding sites for human GH (hGH) were studied in liver membranes of rats with chronic renal insufficiency (CRI) associated with marked growth retardation. A subtotal nephrectomy was performed in young female rats. One month after the nephrectomy, the animals with a plasma creatinine level 3 times or more that of controls were studied; their mean statural gain was 56% that of controls. The specific binding of [125I]hGH to microsomal membranes of rats with CRI was low (40% that of controls). The number of binding sites rather than the affinity of the binding was affected; both the lactogenic and somatotropic sites were decreased, as judged from the binding of ovine [125I]PRL and bovine [125I]GH. The binding sites of the plasma membranes as well as those of the Golgi fractions, were reduced. In plasma membranes of rats with CRI, the specific binding of glucagon was low, and the specific binding of insulin was elevated; these modifications were associated with a high plasma glucagon level and a decreased insulinemia in rats with CRI, but no modification of plasma GH and PRL levels was found. Thus, the hormone level does not appear to regulate the GH-binding sites in this system. The link between the growth defect and the decreased number of GH-binding sites in the liver membranes of rats with CRI remains to be established.

Membranous glomerulonephritis with extra-renal disorders in children.

Thirty of 85 children with membranous glomerulonephritis (MGN) had associated extraglomerular disorders. The relation of these associations to membranous glomerulonephritis (MGN) is discussed. The causal relationship of acute hepatitis (5 cases), persistent hepatitis B antigenemia (6 cases), systemic lupus erythematosus (2 cases) and syphilis (1 case) may be ascertained; in similar conditions a definite antigen (Ag) has been found in MGN deposits. The association with SS or SA hemoglobinopathy (3 cases) ans with a preceding streptococcal infection (4 cases) raises the possible responsibility of renal tubular epithelium (RTE) Ag and of a streptococcal Ag. D-penicillamine therapy (1 case) is a well-known cause of MGN although the acting Ag remains unknown. Four children had serum sickness-like symptoms, two had hematologic disorders and two had proximal tubular dysfunction, one of them with proven anti-tubular and anti-alveolar basement membrane antibodies. A decrease in plasma C4, Clq, and factor B with normal C3 was frequently observed. The multiple Ag previously described as causative of MGN are recalled. The prevalent incidence of HBsAg is stressed, and the necessity for further investigations in patients with MGN in order to find an underlying disease is emphasized.

Optimal dietary substitution of racemic ketoanalogues for isoleucine in growing normal and uremic rats.

Dietary ketoanalogues (KAs) were shown to replace their essential amino acids with a 50% efficiency for valine and leucine. We determined the optimal concentration of the racemic KA of isoleucine (KMVA) in uremic and control rats: nutrition responses were compared between a diet containing optimal isoleucine concentration and diets containing various KMVA concentrations. Isomolar replacement of isoleucine produced anorexia, stunting, and poor nitrogen balance. Doubling KMVA partially improved these indices. Tripling KMVA lessened urea production and improved growth up to that obtained with the isoleucine diet in uremic but not in control rats (20% lower). A further KMVA increase produced no further benefit. Among plasma branched-chain amino acids, only alloisoleucine was affected; it increased with increasing KMVA concentration, being maximum after tripling KMVA. Racemic KMVA could replace isoleucine with a 35% efficiency but supported no growth acceleration in uremic rats and no maximal growth in control rats. Plasma alloisoleucine rose without adverse nutrition effects.

Nutritional effects of feeding a ketoanalogue mixture in growing and adult uremic rats.

Insufficient protein diets supplemented with ketoanalogue/essential amino acid (KA/EAA) mixtures are proposed to maintain nutrition and to retard renal deterioration. We compared in growing and in adult uremic rats diets containing limited or usual amounts of protein (12%, 20% for growing rats, and 10% and 16% for adult rats) with diets containing 50% or 60% less casein plus a KA/EAA mixture providing KA at an equimolar amount of removed EAA or at higher amounts. The latter supplement caused stunting, the former caused no anorexia, a slight growth deficit when added to the lowest basal casein diets, and almost normal growth when added to higher casein diets. Growth was normal with EAA supplements. The plasma EAA changes were unrelated to intake and to growth. Thus, KA utilization is maximal, provided that basal protein is sufficient and KA are not in excess.

Plasma and muscle free amino acids in children at the early stages of renal failure.

Plasma and muscle free amino acid analyses have been performed on four groups of children with different levels of renal failure. Mean plasma creatinine of the groups 1 to 4 was respectively 1.3, 2.3, 3.3, and 4.9 mg/100 ml. Significant but different alterations of plasma and muscle amino acid pattern were found in the four groups of patients. In plasma, aspartic acid, citrulline, OH-proline, 1- and 3-methyl histidine were regularly increased, while threonine, valine, phenylalanine, isoleucine, leucine, tryptophane, tyrosine, and tyrosine/phenylalanine ratio were generally decreased. In muscle, glutamine was usually increased and alanine, valine and valine/glycine ratio decreased; significant increase of total amino acid content was only noted in group 4. Some amino acid alterations became worse with renal failure such as 3-methylhistidine increase or tyrosine/phenylalanine decrease, but group 3 patients had the greatest number of individual amino acid alternations. This group of patients also had the highest protein intake. Relationship between growth velocity and muscle amino acid pattern was found, a poor growth rate was associated with an increase of nonessential and essential amino acids with the exception of valine.

Efficiency of substitution of 2-ketoisocaproic acid and 2-ketoisovaleric acid in the diet of normal and uremic growing rats.

Effects of various intakes of the ketoanalogues of leucine (KICA) and valine (KIVA) on growth, nitrogen, and urea excretion were examined and compared to those of an optimal intake (A) of the corresponding amino acids. Diet KICA and KIVA contents varied from 1 to 4 times A. In controls, growth was significantly reduced with equimolar substitution, corrected with twice A, and unchanged at higher levels. Doubling KICA corrected growth except with substantial anorexia. In uremic rats fed KIVA, growth was corrected at twice A. Low-KICA diets reduced plasma-leucine level; higher KICA diets normalized plasma leucine and revealed branched-chain amino acid (BCAA) antagonism. Changes in 2-ketoacids were unrelated to those of BCAA. In uremia, KICA decreased plasma and urinary urea without changing nitrogen retention. Ketoacid substitution for amino acids was 50% efficient in normal rats and not altered by uremia. BCKAs, specifically KICA, could modify urea metabolism.

Uremia-induced disturbances in hepatic carbohydrate metabolism: enhancement by sucrose feeding.

A high-sucrose (S) diet accentuates anorexia and stunts growth in uremic (U) rats, and an oral S load induces a greater hyperfructosemia in U rats than in control (C) rats. Four studies were performed to determine the roles of S feeding and an acute S load on liver carbohydrate (CHO) metabolism in U and C rats (eight to 10 rats per group). We also examined the plasma responses to either water or a S load. Levels of the main metabolites of glycolysis, gluconeogenesis, and glycogenesis were measured under basal conditions (7 hours' postmeal) in U and C rats fed either a cornstarch diet (study I) or S diet (study II) and at 30 and 60 minutes after an intragastric S load (studies III and IV) in s-fed U and C rats. The weight gain, food intake, and plasma creatinine and urea levels of the rats in the four studies were comparable. Weight gain and liver weight (g/100 g body weight) were lower in U than in C rats. In the plasma, baseline levels of lactate were decreased by uremia and S feeding and those of glucose (G) were increased by S feeding. The increases in plasma G and fructose (F) levels after a S load were greater in U rats than in C rats, whereas those of plasma lactate were comparable. In the liver under basal conditions, uremia markedly decreased levels of glycogen, F-1,6-diphosphate (F-1,6-diP), F-2,6-diP, 3-glycero-phosphate (3-glycero-P), dihydroxyacetone phosphate (DHAP), pyruvate, lactate, and adenosine triphosphate (ATP), and the phosphorylation state (ATP/adenosine diphosphate [ADP] x inorganic phosphorus [PI]), increased phosphoenolpyruvate (PEP), ADP, and Pi levels, but did not affect the cytosolic redox state (pyruvate/lactate). In addition to uremia, S feeding further decreased levels of glycogen, F-2,6-diP, 3-glycero-P, and ATP. After S loading, liver F levels increased more in U than in C rats, but glycogen and 3-glycero-P levels increased less in U than in C rats. Liver lactate and pyruvate levels increased more in U than in C rats, and the pyruvate/lactate and DHAP/3-glycero-P ratios were higher in U than in C rats after a S load. The ATP level and the phosphorylation state in U rats increased 30 minutes later in U than in C rats. Our findings indicate that uremia causes a depletion in liver glycogen, which is enhanced by S feeding and could be partially attributed to decreased glycogen synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Adverse effect of proteins on remnant kidney: dissociation from that of other nutrients.

Several experiments have shown that deterioration of renal parenchyma after reduction of functional mass is affected by the protein content of the diet. The respective role of proteins and that of other nutrients that vary with proteins were never clearly separated. Three groups of 9 uremic rats received diets differing exclusively in protein (casein) content, which was 8% (group 1), 16% (group 2), and 32% (group 3). Energy and minerals were maintained identical. Food intake was similar in groups 1 and 2 and was lower in group 3. Mortality rate remained closely related to protein intake. Of group 3 rats, 78% died within 10 weeks and 100% within 15 weeks. Of group 2 rats, 56% were dead at week 15, and 100% at week 30. Mortality occurred significantly later in group-1 rats fed the lowest protein diet. Histology of remnant kidneys showed severe glomerular and tubular damage, with no or little calcium deposits despite normal phosphorus diet and frequent hyperphosphatemia. These data suggest that protein intake, independent of any other nutrient, influences survival by accelerating the renal damage in rats with reduced kidney mass.

Growth and development of nondialyzed children with chronic renal failure.

Thirty-four children with severe kidney disease, either congenital (32 cases) or developing at birth, were followed until age 5 to 19 years. Overall growth retardation corresponded to -2.5 SD below the mean normal values. The retardation occurred almost exclusively before therapy for it was started. Fifteen children were first treated during infancy. In all of them except one, growth was dramatically improved following the first visit to our center, growth changing from slowed to normal rate, although catch-up growth was rare: the average change from normal mean height was -1.68 SD (or -5 SD per year) calculated for the infantile period up to the first visit to our clinic, followed by a change of +0.18 SD per year between first presentation and age 12 months, and +0.01 SD per year between first presentation and last observation at a mean age of 8.3 years. In the 19 patients who were treated after the first year of life, the mean change of height from birth to first presentation was -0.33 SD per year followed by a mean change of -0.04 SD per year up to the last observation (mean period, 7.3 years). Catch-up growth was exceptional. Five children entered puberty with a normal growth spurt. When GFR deteriorated, growth velocity was unchanged. Height calculated for corresponding bone maturity was reduced in half of the patients when first seen, but progressed to the same degree as height during follow-up, except in one patient. Mental development was normal in 31 of 34 patients. Conclusion. Normal growth rate and normal development is possible in children and even in infants with CRF chronic renal failure. The importance of instituting early conservative treatment to prevent height loss must be emphasized.

Comparison of three low-nitrogen diets containing essential amino acids and their alpha analogues for severely uremic children.

Six infants, 4.5 to 19 months old, whose creatinine clearance was less than 6 ml/min/1.73 m2 received, successively, three low-nitrogen diets. Diet A contained 9.3 g of human milk protein; and diet B, 4.2 g of human milk protein plus synthetic essential amino acids. Diet C was the same as B except that five essential amino acids were replaced by alpha-keto and hydroxy analogs. Serum urea decreased as the infants were transferred from diet A to diets B and C, and the serum urea/creatinine ratio decreased from diet A to diet B and from diet B to diet C. Urea appearance was 14.8 +/- 4.5, 9.1 +/- 4.3, and 6.9 +/- 1.7 mmoles/day, with diets A, B, and C, respectively. Weight gain was also lowest with diet C, as was the difference between nitrogen intake and urea nitrogen appearance, an indicator of nitrogen balance. Plasma free amino acids were not modified by diets A and B, but valine, leucine, and the plasma free essential amino acid pool decreased significantly with diet C.

Perceptions of and preferences for sweet taste in uremic children.

Uremic children have low energy intakes, with little appetite for sweet foods. Likewise, sucrose-rich diets are poorly accepted by uremic rats, which suggests that uremia causes a relative aversion for sucrose. Hemodialyzed children (no. = 39, mean age = 160 mo) and healthy controls (no. = 25, mean age = 122 mo) were compared for perception of sweet taste intensity in two familiar foods (soft white cheese and apple sauce) and for preference for sweetness. The food stimuli were prepared in five sucrose concentrations: 1%, 5%, 10%, 15%, and 20% for cheese; 10%, 20%, 30%, 40%, and 60% for apple sauce. Children were presented with pairs of stimuli of adjacent concentrations and asked, in a forced choice, to identify the sweeter stimulus and to express their preferences. The hemodialyzed children made more mistakes (19%) than the controls (5%) when asked to rank sweetness in the soft cheese (i.e., with low concentrations). Both groups made an equal number of mistakes when asked to rank sweetness in the apple sauce. Preferences for sweetness were markedly different. In cheese, the highest sucrose concentration was preferred by 21.9% of the hemodialyzed children vs 41% of the controls. The lowest sucrose concentration was selected by 15.6% of the hemodialyzed children vs 4.6% of the controls. Similar preference trends were observed for apple sauce. We conclude that abnormally low preferences for sweet foods can contribute to insufficient caloric intake in uremic children.

Growth hormone action is blunted by acidosis in experimental uremia or acid load.

The effects of rhGH (H) daily injection (2 IU/d) and of vehicle (V) during two weeks were studied in young (60 g) growing rats. Experiment I was performed in uremic rats (mean plasma creatinine: 65-71 mumol/l) either acidotic (mean HCO3-:11.5 mmol/l: UAH, n = 20; UAV, n = 18), or with corrected acidosis by addition of NaHCO3 in the diet (mean HCO3-:26 mmol/l: UBH, n = 25; UBV, n = 23). Experiment II used rats with normal renal function (plasma creatinine: 25 mumol/l), either non-acidotic but food restricted to the dietary intake of uremic rats (CRH: n = 18, CRV: n = 18), or rendered acidotic by NH4Cl (CAH: n = 16, CAV: n = 16). GH induced an augmentation of body weight and length gains in non-acidotic uremic rats (+33% and +41%: p < 0.01), and in non-acidotic food restricted rats (+13% and 42%: p < 0.05 and p < 0.0001). This was associated with increased protein synthesis rate in muscle and with little change of food intake as well as of plasma IGF 1. Plasma IGF 1 kept the same relationship to food intake, regardless of treatment, but length gain for each level of plasma IGF 1 was enhanced by GH in GH responding groups. In both acidotic rat groups, GH altered none of the parameters studied. Thus: 1) the presence of severe metabolic acidosis blunts the response to GH in uremic and non-uremic rats. 2) The increment of growth rate does not depend on a rise of plasma IGF 1.

Zinc bone loss in chronic renal failure and chronic metabolic acidosis.

The effects of chronic metabolic acidosis (CMA) on zinc (Zn) bone content and urinary excretion were examined in the presence of normal or reduced renal function together with some aspects of calcium (Ca) metabolism. Four groups of rats were compared. All were fed a 30% protein and 9 mg Zn/100 g diet. Two were uremic (U): The first developed acidosis (UA), which was suppressed in the other (UNA) by NaHCO3 supplement. Two other groups had normal renal function: One was normal (CNA), and the other had NH4Cl in the drinking water and acidosis (CA). Femur total Zn and Ca content was markedly reduced by CMA and was not affected by uremia. Zn urinary excretion was increased by CMA and unaltered by uremia. Ca urinary excretion was markedly reduced in uremic rats, but was enhanced in both acidotic conditions. Urinary Ca and Zn showed a strong correlation in uremic and in control rats. Plasma parathormone and 1,25(OH)2D3 were unchanged by CMA. These data are in agreement with a direct primary effect of CMA on bone in releasing buffers. CMA induces bone resorption and a parallel decrease of mineral bone components, such as Ca and Zn, with little or no role of PTH, 1,25(OH)2D3 and of uremia itself.